The present invention relates to compounds which are non-peptidyl in structure and active as potent inhibitors of the binding of very late antigen-4 (VLA-4; xcex14xcex21; CD49d/CD29) to proteins such as vascular cell adhesion molecule-1 (VCAM-1), the HepII/IIICS domain (CS-1 region) of fibronectin and osteopontin. As such they are useful in the inhibition of cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4. The compounds and pharmaceutical compositions of this invention may be used in the treatment of many inflammatory, autoimmune and respiratory diseases, especially asthma.
One of the most fundamental processes necessary for normal host defence is the regulated trafficking of leukocytes out of the vasculature. This system is designed to allow normal recirculation of leukocytes, yet because it enables the rapid extravasation of leukocytes at sites of injury it is one of the central pathogenic mechanisms of inflammatory, respiratory and autoimmune diseases in mammals. Cell adhesion is a key factor in this process, and it is particularly relevant to the present invention regarding the cell/cell and cell/matrix binding of hematopoietic cells containing VLA-4.
VLA-4 is a member of a superfamily of cell surface macromolecular receptors called integrins, which are non-covalent heterodimeric complexes consisting of an xcex1 subunit and a xcex2 subunit (Hemler, Ann. Rev. Immunol., 8, p.365, 1990). Eighteen different xcex1 subunits have been identified and labeled xcex11-xcex110, xcex1L, xcex1M, xcex1X, xcex1D, xcex1LRI, xcex1IIB, xcex1V and xcex1E; while nine different xcex2 subunits have been identified and labeled xcex21-xcex29. Each integrin molecule can be categorized into a subfamily based on the type of its xcex1 and xcex2 subunits.
The xcex14xcex21 integrin, VLA-4, is an integrin constitutively expressed by all leukocytes (e.g., monocytes, lymphocytes, basophils, eosinophils, mast cells and macrophages) except polymorphonuclear leukocytes. The binding of this integrin to one of its ligands has a number of known cell adhesion and activation functions (Hemler, Ann. Rev. Immunol., 8, p.365, 1990; Walsh et al., Clin. and Exp. Allergy, 25, p. 1128, 1995; Huhtala et al., J. Cell Biol., 129, p. 867, 1995). In particular, it is a receptor for the cytokine-inducible endothelial cell surface protein known as vascular cell adhesion molecule-1 (VCAM-1), and for the alternatively spliced forms of the extracellular matrix protein fibronectin (FN) containing the CS-1 domain (Ruegg et al., J. Cell Biol., 177, p. 179, 1991; Wayner et al., J. Cell Biol., 105, p. 1873, 1987; Kramer et al., J. Biol. Chem., 264, p.4684, 1989; Gehisen et al., Science, 24, p. 1228, 1988). The importance of VLA-4 cell adhesion interactions has been established by the use of specific monoclonal antibody (mAb) antagonists of the xcex1 subunit of VLA-4, which have demonstrated that inhibitors of VLA-4 dependent cell adhesion prevent or inhibit numerous inflammatory, respiratory and autoimmune pathological conditions (Chisholm et al., Eur. J. Immunol., 23, p. 682, 1993; Lobb et al., J. Clin. Invest., 94, p. 1722, 1994; Richards et al., Am. J. Respir. Cell Mol. Biol., 15, p.172, 1996; Soiluhanninen et al., J. Neuroimmunol., 72, p. 95, 1997; Sagara et al., Int. Arch. Allergy Immunol., 112, p.287, 1997; Fryer et al., J. Clin. Invest., 99, p. 2036, 1997). In addition, confirmation that this pathological processes can be inhibited with agents other than antibodies has been observed in animal models following treatment with a synthetic CS-1 peptide or a small molecule peptide inhibitor of VLA-4 (Ferguson et al., Proc. Natl. Acad. Sci., 88, p.8072, 1991; Wahl et al., J. Clin. Invest., 94, p.655, 1994; Molossi et al., J. Clin. Invest., 95, p.2601, 1995; Abraham et al., Am. J. Respir. Crit. Care Med., 156, p. 696, 1997; Jackson et al., J. Med. Chem., 40, p. 3359, 1997).
The investigation of mAb and peptide VLA-4 antagonists in the art has already been noted above. In defining the binding site for xcex14xcex21 it was observed that lymphoid cells can bind to two different sites on fibronectin (Bernardi et al., J. Cell Biol., 105, p. 489, 1987). One component of this cell binding activity has previously been identified as the tripeptide Arg-Gly-Asp (RGD) that binds to the integrin xcex15xcex21 (VLA5). Subsequently, the minimum amino acid sequence required to bind and antagonize the activity of VLA-4 on leukocytes to the alternatively spliced site in fibronectin was determined (Humphries et al., J. Biol. Chem., 266, p.6886, 1987; Garcia-Pardo et al., J. Immunol., 144, p.3361, 1990; Komoriya et al., J. Biol. Chem., 266, p. 15075, 1991). It was discovered that the VLA-4 binding domain in the CS-1 region of fibronectin (FN) comprised the octapeptide: Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr, as well as two overlapping pentapeptides: Glu-Ile-Leu-Asp-Val and Leu-Asp-Val-Pro-Ser. All of these peptides inhibited FN-dependent cell adhesion, leading to the early conclusion that the minimal amino acid sequence required for inhibition was Leu-Asp-Val (LDV). In fact the LDV minimal inhibitory sequence was observed to be equally effective as the full length CS-1 fragment in binding the activated form of VLA-4 (Wayner et al., J. Cell Biol., 116, p. 489, 1992).
Various integrins are believed to bind to extracellular matrix proteins at an Arg-Gly Asp (RGD) recognition site. RGD based cyclic peptides have been made that are said to be able to inhibit both xcex14xcex21 and xcex15xcex21 binding to FN (Nowlin et al., J. Biol. Chem., 268, p. 20352, 1993; PCT/US91/04862) even though the primary recognition on FN for xcex14xcex21 is LDV. The cyclic peptide is: 
where TPro denotes 4-thioproline.
Other peptidyl inhibitors of VLA-4 are those referred to in Arrhenius, T. S.; Elices, M. J.; Gaeta; F. C. A.; xe2x80x9cCS-1 Peptidomimeticsxe2x80x9d, WO 95/15973, wherein a representative compound of the type referred to is the following:
N-Phenylacetyl-Leu-Asp-Phe-NCy3
wherein NCy3 is selected from, inter alia, morpholinamido, thiomorpholinamido, 4-(thiadioxo)piperidinamido, and D-2-(carboxamide)-pyrrolidinamido, piperidinamido, and substituted piperidinamido.
The Leu-Asp-Val tripeptide has been used as the core of a group of inhibitors of VLA-4 dependent cell adhesion of the formula: 
where R1 may be 4-(Nxe2x80x2-(2-methylphenyl)urea)phenylmethyl; Y may be Cxe2x95x90O; R2 may be H; R3 may be iso-butyl; and R14 may be 1,3-benzodioxol-5-yl. See Adams, S. P.; Lin, K.-C.; Lee, W.-C.; Castro, A. C.; Zimmerman, C. N.; Hammond, C. E.; Liao, Y.-S.; Cuervo, J. H.; Singh, J.; xe2x80x9cCell Adhesion Inhibitorsxe2x80x9d, WO 96/22966, which refers to compounds such as the following: 
Other peptidyl inhibitors of VLA-4-mediated cell adhesion which have been reported include those of the formula:
Zxe2x80x94(Y1)xe2x80x94(Y2)xe2x80x94(Y3)nxe2x80x94X
where Z may be 4-(Nxe2x80x2-(2-methylphenyl)urea)phenylacetyl; (Y1)xe2x80x94(Y2)xe2x80x94(Y3)n represents a series of amino acids forming a peptide chain; and X may be OH. See Lin, K.-C.; Adams, S. P.; Castro, A. C.; Zimmerman, C. N.; Cuervo, J. H.; Lee, W.-C.; Hammond, C. E.; Carter, M. B.; Almquist, R. G.; Ensinger, C. L.; xe2x80x9cCell Adhesion Inhibitorsxe2x80x9d, WO 97/03094, which refers to compounds such as the following: 
See further Zheng, Z.; Ensinger, C. L.; Adams, S. P.; WO 98/04247 which refers to cell adhesion inhibitors comprising a compound of the formula: A-B, where A comprises a specificity determinant which does not impart significant IIb/IIIa activity, and B comprises an integrin scaffold. The following compound is representative of those referred to: 
See also Singh, J.; Zheng, Z.; Sprague, P.; Van Vlijmen, H. W. T.; Castro, A.; Adams, S. P.; xe2x80x9cMolecular Model for VLA-4 Inhibitorsxe2x80x9d, WO 98/04913, which refers to a three dimensional pharmacophore model of a compound having VLA-4 inhibitory activity, comprising features defined by a table of tolerances and three dimensional coordinates x, y, and z. The following compound is representative of those referred to: 
Despite the above-described advances in the art with regard to inhibitors of VLA-4 mediated cell adhesion, the artisan will quickly recognize that these peptidyl inhibitors are prone to poor absorption, poor solubility and are subject to metabolism in vivo (both systemically and locally when administered directly into the lung) diminishing their opportunity to appreciably affect the course of an inflammatory, respiratory or autoimmune disease. Accordingly, there still exists in the art a need for non-peptidyl or semi-peptidyl therapeutic agents which can effectively treat or prevent such pathological conditions.
The present invention is concerned with compositions which inhibit VLA-4 dependent cell adhesion in a mammal. The present invention thus relates to a compound of Formula (1.0.0): 
and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein:
A is aryl, heteroaryl, or heterocyclyl as defined herein; where said aryl, heteroaryl, or heterocyclyl is substituted with 0 to 3 R10; or is a member selected from the group consisting of divalent radicals: xe2x80x94A1xe2x80x94NHC(xe2x95x90O)NHxe2x80x94A2xe2x80x94, xe2x80x94A1xe2x80x94NHC(xe2x95x90O)Oxe2x80x94A2xe2x80x94, and xe2x80x94A1xe2x80x94NH(NCN)NHxe2x80x94A2xe2x80x94, where A1 and A2 is each independently selected from the group consisting of hydrogen, aryl, heteroaryl, and heterocyclyl as defined herein, where said aryl, heteroaryl, or heterocyclyl is substituted with 0 to 3 R10 ;
B is a member independently selected from the group consisting of the following: 
xe2x80x83where the symbol xe2x80x9c*xe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.14) to the moiety xe2x80x9cYxe2x80x9d in Formula (1.0.0); and the symbol xe2x80x9cxe2x86x92xe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.14) to the moiety xe2x80x9cExe2x80x9d in Formula (1.0.0);
E is a single bond; xe2x80x94Oxe2x80x94; xe2x80x94CHxe2x95x90CHxe2x80x94; or a moiety of Formula (1.9.0): 
xe2x80x83where R1a is hydrogen when R1 has the meaning of a mono-valent substituent; and R1a is a single bond when R1 has the meaning of a di-valent substituent;
X is xe2x80x94Oxe2x80x94; xe2x80x94S(xe2x95x90O)qxe2x80x94; or xe2x80x94N(R14)xe2x80x94;
Y is xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94C(xe2x95x90S)xe2x80x94; xe2x80x94S(xe2x95x90O)2xe2x80x94; or xe2x80x94CH(Ra)xe2x80x94;
m is an integer independently selected from 0, 1 and 2;
n is an integer independently selected from 1 and 2;
p is an integer independently selected from 1 and 2, provided that p must be selected as 1 where B is selected as partial Formula (1.1.2), (1.1.3), (1.1.5); (1.1.6), (1.1.7), (1.1.8), (1.1.9), (1.1.10), (1.1.11), (1.1.12), (1.1.13) or (1.1.14);
q is an integer independently selected from 0 and 2;
R is independently selected from the group consisting of -tetrazolyl; xe2x80x94C(xe2x95x90O)xe2x80x94OR5; xe2x80x94C(xe2x95x90O)(CH2)kC(xe2x95x90O)OR5; xe2x80x94C(xe2x95x90O)NOxe2x80xa2; xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94S(xe2x95x90O)2R5; xe2x80x94S(xe2x95x90O)2xe2x80x94NR14R5; xe2x80x94C(xe2x95x90O)NHS(xe2x95x90O)2R6; and a moiety of partial Formula (3.0.0): 
xe2x80x83where:
k is an integer independently selected from 0, 1 and 2;
R1 is independently selected from the group consisting of hydrogen; xe2x95x90O; xe2x95x90S; F; (C1-C6) alkyl substituted with 0 to 3 R10; (C2-C6) alkenyl substituted with 0 to 3 R10; (C2-C6) alkynyl substituted with 0 to 3 R10; a (C3-C14) carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12; and aryl(C1-C4) alkyl wherein said aryl and alkyl are substituted with 0 to 3 R12; heterocyclyl as defined herein, substituted with 0 to 3 R12; and heterocyclyl(C1-C4) alkyl as defined herein, wherein said heterocyclyl and alkyl are substituted with 0 to 3 R12; C(xe2x95x90O)NR8R9; and C(xe2x95x90O)R8;
R2 and R3 are each independently selected from the group consisting of hydrogen; (C1-C4) alkyl substituted with 0 to 3 R13; (C2-C6) alkenyl substituted with 0 to 3 R13; a (C3-C14) carbocyclic ring system substituted with 0 to 3 R13; (C1-C4) alkoxycarbonylamino-(C1-C4)alkyl-; (C1-C4) alkylthio-(C1-C4)alkyl-; (C1-C4) alkylsulfonyl-(C1-C4)alkyl-; hydroxy(C1-C4) alkylthio-(C1-C4)alkyl-; (C1-C4) alkylcarbonylamino-(C1-C4)alkyl-; (C1-C4) alkylsulfonylamino-(C1-C4) alkyl-; (C1-C4) alkylsulfonylaminocarbonyl-(C1-C4) alkyl-; and a heterocyclyl ring as defined herein, substituted with 0 to 3 R13; provided that
R2 and R3 are each defined as above; or they are taken together as defined below; or one of them is taken together with R4 as defined below, in which case the other has the meaning of hydrogen or methyl;
R2 and R3 are taken together to form a spirocyclic (C3-C14) carbocyclic ring substituted With 0 to 3 R13; or
R2 or R3 is taken together with R4 and the carbon and nitrogen atoms to which they are respectively attached to form a heteroaryl or heterocyclyl group as defined herein, substituted with 0 to 3 R12;
R5 is hydrogen; (C1-C4) alkyl; (C3-C6) cycloalkyl; or aryl;
R6 is hydrogen; (C1-C4) alkyl; (CH2)rxe2x80x94(C3-C6)cycloalkyl; or (CH2)s-aryl; where:
r and s are each independently an integer selected from 0, 1, and 2;
R8 and R9 are each independently selected from the group consisting of hydrogen; (C1 -C4) alkyl substituted with 0 to 3 R10; a (C3-C14) carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12; and aryl-(C1-C4) alkyl wherein said aryl and alkyl are substituted with 0 to 3 R12; heterocyclyl as defined herein substituted with 0 to 3 R12; and heterocyclyl-(C1-C4) alkyl as defined herein, wherein said heterocyclyl and alkyl are substituted with 0 to 3 R12;
R10 is independently selected from the group consisting of F; Cl; xe2x80x94C(xe2x95x90O)OR14; xe2x80x94OH; nitro; cyano; amino; di(C1-C4) alkylamino; (C1-C4) alkyl; (C1-C4) alkoxy; (C1-C4) alkylthio; phenoxy; trifluoromethoxy; (C3-C6) cycloalkyl; (C3-C6) cycloalkoxy; (C3-C6) cycloalkoxycarbonyl; (C1-C4) alkylcarbonylamino; (C1-C4) alkylsulfonylamino; (C1-C4) alkylurea; and (C1-C4) alkyl and (C1-C4) alkoxy each substituted with 1 to 3 substituents independently selected from F and Cl;
R12 when a substituent on a carbon atom, is independently selected from the group consisting of F; Cl; (C1-C4) alkyl; (C3-C6) cycloalkyl; (C1-C4) alkoxy; xe2x80x94C(xe2x95x90O)OR14; xe2x80x94OH; (C1-C4) alkyl and (C1-C4) alkoxy each substituted with 1 to 3 substituents independently selected from F and Cl; (C1-C4) alkoxycarbonyl; (C1-C4) alkylcarbonyl; (C1-C4) alkylcarbonyloxy; and a heteroaryl or heterocyclyl group as defined herein which is 5- or 6-membered; or
R12 when two R12 groups are attached to adjacent carbons of a carbocyclic, aryl, heteroaryl, or heterocyclic ring, may be a 3- or 4-carbon chain which forms a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally mono- or di-substituted on the aliphatic carbon atoms thereof with F, Cl, (C1-C4) alkyl, (C1-C4) alkoxy, or hydroxy; or
R12 when R12 is attached to a saturated carbon atom, may be xe2x95x90O or xe2x95x90S; or when R12 is attached to a sulfur atom, may be xe2x95x90O;
R12 when a substituent on a nitrogen atom, is independently selected from the group consisting of hydroxy; hydroxy(C1-C4) alkyl; (C1-C4) alkoxy; (C3-C6) cycloalkyl; (C1-C4) alkylcarbonyl; and aryl;
R13 is independently selected from the group consisting of aryl; heteroaryl; heterocyclyl; (C1-C4) alkoxy; (C3-C6) cycloalkyl; (C2-C6) alkynyl; xe2x80x94OR14; heterocyclyl-carbonyl; (C1-C4) alkylthio; xe2x80x94NR6R5; and xe2x80x94C(xe2x95x90O)NR14R5; and
R14 is hydrogen; hydroxy; (C1-C4) alkyl; (C3-C6) cycloalkyl; or aryl
The present invention is also concerned with pharmaceutical compositions comprising one or more of the compounds of the present invention as described above together with a pharmaceutically acceptable carrier for said compound(s), wherein the amount of said compound(s) present is effective for preventing, inhibiting, suppressing or reducing cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4. The present invention is further concerned with pharmaceutical compositions which in addition to containing a compound of the present invention, additionally comprise one or more therapeutic agents selected from the group consisting essentially of anti-inflammatory corticosteroids, nonsteroidal anti-inflammatory agents, bronchodilators, anti-asthmatic agents, and immunosuppressant agents.
The present invention is still further concerned with a method of treating or preventing an inflammatory, autoimmune or respiratory diseases by inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the present invention. The pharmaceutical compositions of the present invention may be used in the treatment of many inflammatory, autoimmune and respiratory diseases, including but not limited to asthma, multiple sclerosis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, host rejection following organ transplantation, atherosclerosis, and other diseases mediated by or associated with VLA-4.
The present invention relates to compounds which inhibit cell adhesion and subsequent pathogenic processes mediated by VLA-4. These compounds, which are thus useful in the treatment of many inflammatory, autoimmune amd respiratory diseases, may be illustrated by Formula (1.0.0): 
For compounds of Formula (1.0.0), the terminal group identified as A has the meaning aryl, heteroaryl, or heterocyclyl substituted with 0 to 3 R10, or is a member selected from the group consisting of divalent radicals: xe2x80x94A1xe2x80x94NHC(xe2x95x90O)NHxe2x80x94A2xe2x80x94, xe2x80x94A1xe2x80x94NHC(xe2x95x90O)Oxe2x80x94A2xe2x80x94, and xe2x80x94A1xe2x80x94NH(NCN)NHxe2x80x94A2xe2x80x94, where A1 and A2 is each independently selected from the group consisting of hydrogen, aryl, heteroaryl, and heterocyclyl, where said aryl, heteroaryl, or heterocyclyl is substituted with 0 to 3 R10.
The term xe2x80x9carylxe2x80x9d as used with reference to xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, is intended to refer to a carbocyclic aromatic group which is a member selected from the group consisting essentially of phenyl, naphthyl, indenyl, indanyl, and fluorenyl. It is preferred, however, that where xe2x80x9cAxe2x80x9d is xe2x80x9carylxe2x80x9d, that it is phenyl.
The term xe2x80x9cheteroarylxe2x80x9d as used with reference to xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, is intended to refer to a heterocyclic aromatic group which is a member selected from the group consisting essentially of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyranyl, parathiazinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pyrazolo[1,5-c]triazinyl.
It is preferred, however, that where xe2x80x9cAxe2x80x9d is xe2x80x9cheteroarylxe2x80x9d that it is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, benzo[b]furanyl, benzimidazolyl, or quinolinyl. More preferably, xe2x80x9cAxe2x80x9d is pyridyl.
The terms xe2x80x9cheterocylicxe2x80x9d and xe2x80x9cheterocyclylxe2x80x9d as used with reference to xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, are both intended to refer to a non-aromatic 3- to 10-membered carbocyclic ring in which at least one of the carbon atoms of the ring has been replaced by a heteroatom selected from N, O or S. Preferably two, and more preferably one heteroatom is present, except that in the case of nitrogen, as many as four N heteroatoms may be present. The heterocyclyl group may comprise one or two fused rings, and further may include an aryl-fused ring. In a prefered meaning, xe2x80x9cheterocyclylxe2x80x9d refers to a member selected from the group consisting essentially of oxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and benzodioxolane, especially 1,3-benzodioxol-5-yl.
It is preferred, however, that where xe2x80x9cAxe2x80x9d is xe2x80x9cheterocyclylxe2x80x9d that it is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
Where xe2x80x9cAxe2x80x9d is defined as a moiety selected from the above-defined aryl, heteroaryl, or heterocyclyl groups, said moiety may be substituted with 0 to 3 R10. The choice of xe2x80x9c0xe2x80x9d merely denotes that there are no substituents, substitution being optional. Where substitution occurs, preferably there are two substituents, and more preferably there is only one substituent.
Where a substituent R10 is used, it will be independently selected from the group consisting essentially of F; Cl; xe2x80x94C(xe2x95x90O)OR14; xe2x80x94OH; nitro; cyano; amino; di(C1-C4) alkylamino; (C1-C4) alkyl; (C1-C4) alkoxy; (C3-C6)cycloalkyl; (C3-C6)cycloalkoxy; (C1-C4) alkylthio; phenoxy; trifluoromethoxy; (C3-C6) cycloalkoxycarbonyl; (C1-C4) alkylcarbonylamino; (C1-C4) alkylsulfonylamino; (C1-C4) alkylurea; and (C1-C4)alkyl and (C1-C4)alkoxy each substituted with 1 to 3 substituents independently selected from F and Cl; where R14 is as further defined herein. Preferably, however, there is a single substituent and it is F, Cl, OH, methyl, methoxy, cyclohexyl, cyclopropyloxy, or F3Cxe2x80x94.
The term xe2x80x9calkylxe2x80x9d as used with reference to the substituents xe2x80x9cR10xe2x80x9d on the group xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, and whether used alone or in combination, refers to a straight-chain or branched chain alkyl radical containing the indicated number of carbon atoms, usually from 1 to 6 but often from 1 to 4, carbon atoms. Examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl.
The term xe2x80x9calkoxyxe2x80x9d as used with reference to the substituents xe2x80x9cR10xe2x80x9d on the group xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, and whether used alone or in combination, refers to an alkyl ether radical, wherein the term xe2x80x9calkylxe2x80x9d is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
The term xe2x80x9ccycloalkylxe2x80x9d as used with reference to the substituents xe2x80x9cR10xe2x80x9d on the group xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, and whether used alone or in combination, refers to a cyclic alkyl radical containing from 3 to 6 carbon atoms. Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9ccycloalkyloxyxe2x80x9d as used with reference to the substituents xe2x80x9cR10xe2x80x9d on the group xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, and whether used alone or in combination, refers to a cycloalkyl ether radical wherein the term xe2x80x9ccycloalkylxe2x80x9d is as defined above. Examples of such cycloalkyloxy radicals include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
A preferred meaning of xe2x80x9cAxe2x80x9d is that of a ureido radical, more preferably a divalent radical which is a member selected from the group consisting of xe2x80x94A1xe2x80x94NHC(xe2x95x90O)NHxe2x80x94A2xe2x80x94, xe2x80x94A1xe2x80x94NHC(xe2x95x90O)Oxe2x80x94A2xe2x80x94, and xe2x80x94A1xe2x80x94NH(NCN)NHxe2x80x94A2xe2x80x94, where A1 and A2 is each independently selected from the group consisting of hydrogen, aryl, heteroaryl, and heterocyclyl, where said aryl, heteroaryl, or heterocyclyl is substituted with 0 to 3 R10. The aryl, heteroaryl or heterocyclyl group which is bonded to one or both sides of the ureido radical is selected in accordance with the definitions set out above, as are the 0 to 3 substituents R10. It is preferred that an aryl group be covalently bonded to the both sides of the ureido radical, and it is further preferred that this aryl group be phenyl. It is most preferred that said phenyl group have a single substituent which is preferably F, Cl, methyl, methoxy, or F3Cxe2x80x94. Examples of the preferred meanings of xe2x80x9cAxe2x80x9d are shown in partial Formulas (4.0.0) though (4.0.11): 
The component of the compounds of Formula (1.0.0) which is immediately adjacent to the xe2x80x9cAxe2x80x9d component, is the methylene or ethylene bridging element where n=1 or 2, respectively. It is preferred that n=1 and that there be a methylene bridge. Accordingly, within the context of the above-stated preferences for the meaning of the xe2x80x9cAxe2x80x9d component, and adding the methylene bridge, the following most preferred termini which include the component xe2x80x9cAxe2x80x9d, may be represented by the following partial Formulas (4.1.0) through (4.1.23):
It will be further noted partial structural formulas that the preferred methylene bridge is also preferably attached to the N,Nxe2x80x2-diphenylureido group in a para relationship to the point of attachment of the divalent ureido group to the phenyl group involved.
The xe2x80x9cYxe2x80x9d component of Formula (1.0.0) may be xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94; xe2x80x94S(xe2x95x90O)2xe2x80x94; or xe2x80x94CH(Ra)xe2x80x94; where Ra has the meaning of hydrogen or (C1-C4) alkyl. Where xe2x80x9cYxe2x80x9d is the moiety xe2x80x94CH(Ra)xe2x80x94, it is preferred that Ra have the meaning of hydrogen or methyl. Overall, however, it is most preferred that xe2x80x9cYxe2x80x9d be a carbonyl moiety, ie., that xe2x80x9cYxe2x80x9d is the moiety xe2x80x94C(xe2x95x90O)xe2x80x94.
The next component, the xe2x80x9cBxe2x80x9d group of the compounds of Formula (1.0.0) is one of the more important portions of the molecule and is a key element in providing the unexpectedly good biological properties possessed by the compounds of the present invention. The xe2x80x9cBxe2x80x9d group comprises a member selected from the group consisting of partial Formulas (1.1.0) through (1.1.14): 
where the symbol xe2x80x9c*xe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.14) to the moiety xe2x80x9cYxe2x80x9d in Formula (1.0.0); and the symbol xe2x80x9cxe2x86x92xe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.14) to the moiety xe2x80x9cExe2x80x9d in Formula (1.0.0).
All of the above partial Formulas (1.1.0) through (1.1.14) inclusive are illustrated as fragments in the manner above-described, wherein the points of attachment at either end of a particular fragment are indicated by the symbols xe2x80x9c*xe2x80x9d and xe2x80x9cxe2x86x92xe2x80x9d.
In the above partial formulas defining the B component of the compounds of Formula (1.0.0), the moiety xe2x80x9cXxe2x80x9d may be oxygen; sulfur (q=0) and sulfur to which two oxygen atoms is attached (q=2), ie., sulfonyl; or nitrogen (R14=hydrogen) or nitrogen which is substituted (R14=(C1-C4)alkyl; (C3-C6)cycloalkyl; or aryl). It is preferred, however, that xe2x80x9cXxe2x80x9d be simply oxygen, sulfur or nitrogen.
In the above partial formulas defining the B component of the compounds of Formula (1.0.0), R2 and R3 are independently selected from the group consisting of hydrogen; (C1-C4) alkyl substituted with 0 to 3 R13; (C2-C6) alkenyl substituted with 0 to 3 R13; a (C3-C14) carbocyclic ring system substituted with 0 to 3 R13; (C1-C4)alkoxycarbonylamino-(C1-C4)alkyl-; (C1-C4)alkylthio-(C1-C4)alkyl-; (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl-; hydroxy(C1-C4)alkylthio-(C1-C4)alkyl-; (C1-C4)alkylcarbonylamino-(C1-C4)alkyl-; (C1-C4)alkylsulfonylamino-(C1-C4)alkyl-; (C1-C4)alkylsulfonylaminocarbonyl-(C1-C4)alkyl-; and a heterocyclyl ring substituted with 0 to 3 R13; provided that R2 and R3 are not both hydrogen at the same time. This proviso is also satisfied where R2 and R3 are taken together in accordance with an optional definition of R2 and R3, in which case they form a spirocyclic (C3-C14) carbocyclic ring substituted with 0 to 3 R13. For example, where R2 and R3 are taken together to form a spirocyclic cyclopropyl, cyclobutyl, or cyclopentyl group, the resulting compounds of the present invention will include moieties such as those of partial Formulas (1.2.0) through (1.2.2): 
Another preferred sub-group of compounds of the present invention is that formed when either R2 or R3 is taken together with R4 and the carbon and nitrogen atoms to which they are respectively attached to form a heteroaryl or heterocyclyl group as defined herein. Said heteroaryl or heterocyclycl group may, in turn, be substituted with 0 to 3 R12. In accordance with the above-mentioned proviso, when either R2 or R3 is taken together with R4, the other must be hydrogen or methyl. The sub-group may be represented by partial Formula (1.3.0) as follows: 
where the symbol xe2x80x9c*xe2x80x9d indicates the point of attachment of the moiety represented by partial Formula (1.3.0) to the moiety xe2x80x9cYxe2x80x9d in Formula (1.0.0); and the symbol xe2x80x9cxe2x86x92xe2x80x9d indicates the point of attachment of the moiety represented by partial Formula (1.3.0) to the remaining portion of the moiety xe2x80x9cBxe2x80x9d in Formula (1.0.0), defined by partial Formulas (1.1.0) through (1.1.14). The substituent xe2x80x9cR2/3xe2x80x9d indicates the presence of either the R2 substituent or the R3 substituent. They both may not be present, since one or the other has already been selected to be taken together with R4 to form the heteroaryl or heterocyclyl group of partial Formula (1.3.0), represented as follows: 
It will be understood that whether R2 or R3 is present, it will have the meaning of hydrogen or methyl.
Accordingly, this sub-group of the group xe2x80x9cBxe2x80x9d represented by partial Formula (1.3.0) includes, but is not limited to, the embodiments which are represented by partial Formulas (1.3.1) through (1.3.20): 
where the symbol xe2x80x9c*xe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.3.1) through (1.3.20) to the moiety xe2x80x9cYxe2x80x9d in Formula (1.0.0); and the symbol xe2x80x9cxe2x86x92xe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.3.1) through (1.3.20) to the moiety xe2x80x9cExe2x80x9d in Formula (1.0.0).
With reference to the optional substituent R13 which may be present on the R2 and R3 substituents of the B component, R13 is absent when xe2x80x9c0xe2x80x9d is selected. It is preferred that R13 either be absent or be present as a single substituent selected from aryl; heteroaryl; heterocyclyl; (C1-C4)alkoxy; (C3-C6)cycloalkyl; (C2-C6)alkynyl; xe2x80x94OR14; heterocyclyl-carbonyl; (C1-C4)alkylthio; xe2x80x94NR14R5; and xe2x80x94C(xe2x95x90O)NR14R14xe2x80x2. With reference to the optional substituent R13, but also with reference to the remainder of the instant specification, the term xe2x80x9calkynylxe2x80x9d alone or in combination, refers to a straight-chain or branched-chain alkynyl radical containing from 2 to 6, preferably 2 to 4 carbon atoms. Examples of such radicals include, but are not limited to, ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
The term xe2x80x9calkylthioxe2x80x9d, alone or in combination with other terms, is used herein to refer to a thioether radical of the formula alkyl-Sxe2x80x94, where the alkyl component thereof is a straight-chain or branched-chain alkyl radical containing from 1 to 4 carbon atoms, and preferably from 1 to 2 carbon atoms. Thus, an example of such an alkylthio substituent includes, but is not limited to, methylthio and iso-butylthio.
Regarding the definitions of the substituents R2 and R3 on component B, the term xe2x80x9calkoxycarbonylaminoalkylxe2x80x9d, alone or in combination, refers to a radical of formula alkyl-OC(xe2x95x90O)NH-alkyl-, wherein both of the terms xe2x80x9calkylxe2x80x9d are as defined above. The term xe2x80x9calkylthioalkylxe2x80x9d, used alone or in combination, refers to a thioether radical joined to the B component by an alkyl moiety, of the formula alkyl-S-alkyl-, wherein both of the terms xe2x80x9calkylxe2x80x9d are as defined above. The term xe2x80x9calkylsufonylalkylxe2x80x9d, alone or in combination, refers to a radical of the formula alkyl-S(xe2x95x90O)2-alkyl-, wherein both of the terms xe2x80x9calkylxe2x80x9d are as defined above. The term xe2x80x9calkylcarbonylaminoxe2x80x9d, alone or in combination, refers to a radical of formula alkyl-C(xe2x95x90O)NH-alkyl-, wherein both of the terms xe2x80x9calkylxe2x80x9d are as defined above. The term xe2x80x9calkylsulfonylaminoalkylxe2x80x9d, alone or in combination, refers to a radical of formula alkyl-S(xe2x95x90O)2xe2x80x94NH-alkyl-, wherein both of the terms xe2x80x9calkylxe2x80x9d are as defined above. The term xe2x80x9c(C1-C4) alkylsulfonylaminocarbonyl-(C1-C4) alkyl-xe2x80x9d, alone or in combination, refers to a radical of formula alkyl-S(xe2x95x90O)2xe2x80x94NHxe2x80x94C(xe2x95x90O)-alkyl, wherein both of the terms xe2x80x9calkylxe2x80x9d are as defined above.
With reference to component xe2x80x9cBxe2x80x9d of the compounds of Formula (1.0.0), the term xe2x80x9calkenylxe2x80x9d, used in this as well as in other contexts throughout the instant specification, used alone or in combination, is intended to refer to a straight-chain or branched-chain alkenyl radical containing from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-propenyl, iso-propenyl, E- and Z-butenyl, E- and Z-iso-butenyl, and E- and Z-pentenyl.
The term xe2x80x9c(C3-C14)carbocyclic ring systemxe2x80x9d as used with reference to xe2x80x9cBxe2x80x9d, as well as in other contexts throughout the instant specification, used alone or in combination, is intended to refer to cycloalkyl and cycloalkenyl groups consisting of one, two or three fused rings containing a total of from three to fourteen carbon atoms. The term xe2x80x9ccycloalkylxe2x80x9d in turn, means a cyclic alkyl radical containing from 3 to 8, preferably from 3 to 6, carbon atoms. Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term xe2x80x9ccycloalkenylxe2x80x9d on the other hand, refers to a cyclic carbocycle containing from 4 to 8, preferably 5 or 6, carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, and cyclopentadienyl.
Where two or three fused rings are present, one of the rings may be a cycloalkyl ring system while the other one or two rings may be cycloalkenyl ring systems.
It is preferred that when one of R2 and R3 is hydrogen that the other be selected from the group consisting essentially of iso-propyl, sec-butyl, iso-butyl, and tert-butyl; E- and Z-iso-butenyl, and E- and Z-pentenyl; cyclopentyl and cyclohexyl; cyclohexenyl, and cyclopentadienyl; phenyl, indenyl and indanyl; 2-(methylthio)ethyl; 3-(hydroxypropylthio)methyl; 2-(methylsulfonyl)ethyl; 4-(acetylamino)butyl; 4-(methylsulfonylamino)butyl; and 4-ethoxycarbonylamino)butyl.
Attached to component B in the compounds of Formula (1.0.0) are the remaining structural elements which may be represented by partial Formula (1.4.0): 
It will be noted first that the moiety represented by partial Formula (I) is directly attached to component B in the overall compound of Formula (1.0.0), and that p is an integer independently selected from 1 and 2, so that either one or two of the moieties of Formula (1.4.0) may be attached to component B. Ordinarily, in the preferred embodiments of the compounds of Formula (1.0.0) xe2x80x9cpxe2x80x9d will be selected as the integer 1. Moreover, certain partial Formula (1.1.2) etc. definitions of B do not permit xe2x80x9cpxe2x80x9d to be selected as the integer 2. Accordingly, the definition of xe2x80x9cpxe2x80x9d carries with it the proviso that xe2x80x9cp must be selected as 1 where B is selected as partial Formula (1.1.2), (1.1.3), (1.1.5); (1.1.6), (1.1.7), (1.1.8), (1.1.9), (1.1.10), (1.1.11), (1.1.12), (1.1.13) or (1.1.14). Nevertheless, there are embodiments of the compounds of Formula (1.0.0) in which xe2x80x9cpxe2x80x9d will be selected as the integer 2. An example of such a compound is represented by Formula (1.6.0): 
E is a single bond; oxygen; 1,1-cyclopropyl; C(CH3)2; CF2; or is a bridging moiety of partial Formula (1.9.0): 
Where E is defined as a single bond, a particular group of compounds of Formula (1.0.0) is provided for which is characterized by a carboxylic acid or carboxylic acid fragment terminus of reduced size. Thus, where xe2x80x9cmxe2x80x9d is selected as the integer 0, the terminus attached to component B comprises the moiety: [xe2x80x94R]p in which xe2x80x9cpxe2x80x9d would preferably be selected as the integer 1.
In most of the preferred embodiments of the present invention, however, E is defined as the bridging moiety of partial Formula (1.9.0) above. This bridging moiety comprises a substituted methylene group to which is attached substituent R1 and R1a, where R1a is hydrogen when R1 has the meaning of a mono-valent substituent; and R1a is a single bond when R1 has the meaning of a di-valent substituent. In the most preferred embodiments when R1 is a di-valent substituent, it has the meaning xe2x95x90O. A representative compound of the present invention in which E has the meaning of partial Formula (1.9.0), R1a is a single bond, and R1 has the meaning of the di-valent substituent xe2x95x90O, is that represented by Formula (1.4.2): 
In the portions of the compounds of the present invention represented by partial Formula (1.4.0) above, the moiety E is followed by an optional methylene or ethylene bridge: (xe2x80x94CH2xe2x80x94)m where m is an integer independently selected from 0, 1 and 2. It is preferred that an ethylene bridge be present, and it is even more preferred that a methylene bridge be present. In effect the preferred compounds of the present invention thus have an ethylene or propylene bridge between the xe2x80x9cBxe2x80x9d and xe2x80x9cRxe2x80x9d components of Formula (1.0.0) and substituent R1 is therefore attached at the xcex1-position of this ethylene or propylene bridge. It is possible for the R1 substituent to be absent, i.e., for R1 to be hydrogen, and this is the preferred structure in many of the compounds of Formula (1.0.0). Nevertheless, there are a number of other compounds of Formula (1.0.0) in which it is preferred that the R1 substituent be present.
Accordingly, R1 is selected from, in addition to hydrogen, the following: xe2x95x90O; xe2x95x90S; F; CF3; (C1-C6)alkyl substituted with 0 to 3 R10; (C2-C6)alkenyl substituted with 0 to 3 R10; (C2-C6)alkynyl substituted with 0 to 3 R10; a (C3-C14)carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12, and aryl(C1-C4)alkyl wherein said aryl and alkyl are substituted with 0 to 3 R12; heterocyclyl substituted with 0 to 3 R12; and heterocyclyl(C1-C4)alkyl wherein said heterocyclyl and alkyl are substituted with 0 to 3 R12; and C(xe2x95x90O)NR8R9, and C(xe2x95x90O)R8.
The groups (C1-C6)alkyl and (C2-C6)alkenyl have already been defined in detail above. Within the meaning of these groups it is preferred that R1 be methyl, ethyl, iso-propyl, tert-butyl, 2-propenyl, or 1-, 2-, or 3-butenyl.
R1 may also be (C2-C6)alkynyl. The term xe2x80x9calkynylxe2x80x9d as used with reference to xe2x80x9cR1xe2x80x9d, as well as in other contexts throughout the instant specification, used alone or in combination, refers to a straight-chain or branched-chain alkynyl radical containing from 2 to 6 carbon atoms. Examples of such radicals include, but are not limited to, ethynyl (acetylenyl), 1-propynyl, propargyl (2-propynyl), butynyl and hexynyl. Where R1 is alkynyl, it is preferred that it be ethynyl or propargyl
R1 may also be a (C3-C14)carbocyclic ring system substituted with 0 to 3 R12. The meaning of xe2x80x9c(C3-C14)carbocyclic ring systemxe2x80x9d has already been described in detail above, but it is preferred that where R1 is selected from this group, that it be cyclopropyl or cyclopentyl.
R1 may further be aryl substituted with 0 to 3 R12; or aryl(C1-C4)alkyl wherein said aryl and alkyl are substituted with 0 to 3 R12. The meaning of xe2x80x9carylxe2x80x9d and of xe2x80x9c(C1-C4)alkylxe2x80x9d have already been described in detail above, but it is preferred that where R1 is selected from this group, that it be phenyl, phenylmethyl or phenylethyl. Preferred embodiments within these definitions are those which include one or two R12 groups as substituents.
The choice of R12 substituent depends on the location of the R12 substituent. In this case the R12 substituent is located on an aryl or arylalkyl group, and thus will be attached to a carbon atom. When R12 is a substituent on a carbon atom, it is independently selected as a member from among several groups, one of which consists essentially of F; Cl; (C1-C4)alkyl; (C3-C6)cycloalkyl; (C1-C4)alkoxy; xe2x80x94C(xe2x95x90O)OR14; xe2x80x94OH; (C1-C4)alkyl and (C1-C4)alkoxy, each substituted with 1 to 3 substituents independently selected from F and Cl; (C1-C4)alkoxycarbonyl; (C1-C4)alkylcarbonyl; and (C1-C4)alkylcarbonyloxy. Particularly preferred substituents from this group are methyl, methoxy, F, Cl, and xe2x80x94OH.
Another group whose members may define R12 when attached to a carbon atom consists essentially of a 5- or 6-membered heteroaryl or heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur; and a 3- or 4-carbon chain attached to adjacent carbons where an aryl ring to form a fused 9- or 10-membered ring, said 9- or 10-membered fused ring being optionally mono- or di-substituted on the aliphatic carbon atoms thereof with F, Cl, (C1-C4)alkyl, (C1-C4)alkoxy, or hydroxy. Preferred heteroaryl substituents comprising R12 in this group are furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, parathiazinyl, indolyl, benzo[b]furanyl, benzimidazolyl, benzthiazolyl, quinolinyl, and isoquinolinyl. More preferably, R12 is pyrrolyl, imidazolyl, oxazolyl or indolyl. Preferred heterocyclyl substituents comprising R12 in this group are oxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and benzodioxolane, especially 1,3-benzodioxol-5-yl. It is more preferred that where R12 is heterocyclyl that it is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
When R12 is attached to a saturated carbon atom, it may be xe2x95x90O or xe2x95x90S; or when R12 is attached to a sulfur atom, it may be xe2x95x90O. Especially preferred are ketones formed from hetercyclyl substituents, e.g., the pyrrolidinones, pyrazolidinones, imidazolidinones, tetrazolidinones, piperidinones, and piperazinones. Where R12 is attached to a sulfur atom and is defined as (xe2x95x90O)1 or 2, it is preferred that there be two (xe2x95x90O), affording a sulfonyl group.
When R12 is a substituent on a nitrogen atom, it is independently selected from the group consisting essentially of hydroxy; hydroxy(C1-C4)alkyl; (C1-C4)alkoxy; (C3-C6)cycloalkyl; (C1-C4)alkylcarbonyl; and aryl.
Above-mentioned substituent R1 in partial Formula (1.9.0), which in turn represents one of the meanings of basic component E of the compounds of Formula (1.0.0), may be further defined as heterocyclyl substituted with 0 to 3 R12; and heterocyclyl(C1-C4)alkyl wherein said heterocyclyl and alkyl are substituted with 0 to 3 R12. The optional R12 substituents on these heterocyclyl and heterocyclylalkyl groups are as described further above. A particular and preferred meaning of heterocyclyl is that of a benzo-fused ring system comprising a dioxolane, for example where R1 is 1,3-benzodioxol-5-yl. This particular heterocyclyl group is viewed as being structurally analogous to a 3,4-dimethoxyphenyl group, a 3,4-difluorophenyl group, or a benzo-1,4-dioxanyl group, as illustrated by their respective partial Formulas (3.1.0), (3.1.1), (3.1.2), and (3.1.3): 
The R1 basic component of the compounds of Formula (1.0.0) may also be C(xe2x95x90O)NR8R9 or C(xe2x95x90O)R8, where R8 and R9 are independently selected from hydrogen; (C1-C4)alkyl substituted with 0 to 3 R10; a (C3-C14)carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12; and aryl(C1-C4)alkyl wherein said aryl and alkyl are substituted with 0 to 3 R12; heterocyclyl substituted with 0 to 3 R12; and heterocyclyl(C1-C4)alkyl wherein said heterocyclyl and alkyl are substituted with 0 to 3 R12. The R10 and R12 substituents are as described further above.
Finally, the xe2x80x9cRxe2x80x9d component of Formula (1.0.0) is independently selected from the group consisting of -tetrazolyl; xe2x80x94C(xe2x95x90O)xe2x80x94OR5; xe2x80x94C(xe2x95x90O)(CH2)kC(xe2x95x90O)OR5; xe2x80x94C(xe2x95x90O)NOxe2x80xa2; xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94S(xe2x95x90O)2R5; xe2x80x94S(xe2x95x90O)2xe2x80x94NR14R5; xe2x80x94C(xe2x95x90O)NHS(xe2x95x90O)2R6; and a moiety of partial Formula (3.0.0): 
It is preferred that R is C(xe2x95x90O)xe2x80x94OH. However, in addition to such simple carboxylic acids, other preferred embodiments of R include xcex1-, xcex2- and xcex3-keto acids included within the scope of the partial formula: xe2x80x94C(xe2x95x90O)(CH2)kC(xe2x95x90O)OR5. Where k is 0, an xcex1-keto acid such as pyruvic acid is included. Where k is 1, a xcex2-keto acid such as acetoacetic acid is included. Where k is 2, a xcex3-keto acid such as levulinic acid is included.
The R component also includes moieties derived from sulfamic acid, H2NSO3H, defined by the partial formula: xe2x80x94S(xe2x95x90O)2xe2x80x94NR14R5, as well as sulfonamidocarbonyl moieties defined by the partial formulas: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94S(xe2x95x90O)2R5 and xe2x80x94C(xe2x95x90O)NHS(xe2x95x90O)2R6.
Included within the scope of the present invention are the pharmaceutically acceptable derivatives of the compounds of Formula (1.0.0). The expression xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d as used in the instant specification denotes any pharmaceutically acceptable salt of a compound of Formula (1.0.0). Further included within the scope of the present invention is any other compound which, upon administration to a patient, is capable of directly or indirectly providing a compound of Formula (1.0.0). Such compounds are recognized as prodrugs, and a number of established procedures are available for preparing such prodrug forms of the compounds of Formula (1.0.0).
The term xe2x80x9cpatientxe2x80x9d as used above and throughout the instant specification, refers to mammals, including humans. And where the term xe2x80x9ccellxe2x80x9d is used it refers to mammalian cells, including human cells, unless otherwise specified.
Further included within the scope of the present invention are metabolites or residues of the compounds of Formula (1.0.0) which possess biological activity such that they are able to inhibit cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4. Once synthesized, the inhibitory activities and VLA-4 specificities of the compounds of Formula (1.0.0) according to this invention may be determined using in vitro and in vivo assays which are described in detail further below.
The desirable biological activity of the compounds of Formula (1.0.0) may also be improved by appending thereto appropriate functionalities which will function to enhance existing biological properties of the compound, improve the selectivity of the compound for the existing biological activities, or add to the existing biological activities further desirable biological activities. Such modifications are known in the art and include those which increase biological penetration into a given biological system, e.g., blood, the lymphatic system, and central nervous system; increase oral availability; increase solubility to allow administration by injection; alter metabolism; and alter the rate of excretion of the compound of Formula (1.0.0).
In view of the above definitions and others throughout the instant specification, other chemical and biological terms used herein can be easily understood by those of skill in the art. The defined terms may be used alone or in any combination thereof. The preferred and more preferred chain lengths of the radicals which have been specified herein apply to all such combinations.
Further pursuant to the descriptions above of certain preferred subgeneric and more preferred subgeneric definitions of the compounds of Formula (1.0.0), there follows an enumeration of preferred and more preferred species in order to provide a further illustration of the present invention.
Compounds which include the moiety of partial Formula (1.1.0):
3-[2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)4,5-dihydro-oxazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[4-(3-{2-fluorophenyl}-ureido)-phenyl]-acetylamino}-butyl)-4,5 -dihydro-oxazol-5-yl]-propionic acid;
2-[2-(3-Methyl-1-{2-[4-(3-{2-cyclopentylphenyl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-oxazol-5-yl]-acetic acid;
4-[2-(3-Methyl-1-{2-[4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-oxazol-5-yl]-butyric acid;
3-[2-(3-Methyl-1-{2-[4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-oxazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-oxazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methyl-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-thiazol-5-yl]-propionic acid;
2-[2-(3-Methyl-1-{2-[3-fluoro-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-thiazol-5-yl]-acetic acid;
3-[2-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1,1-dioxo-4,5-dihydro-thiazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]--acetylamino}-butyl)-4,5-dihydro-imidazol-5-yl]-propionic acid;
4-[2-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl-acetylamino}-butyl)-4,5-dihydro-imidazol-5-yl]-butyric acid;
3-[2-(3-Methyl-1-{2-[3-methyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-imidazol-5-yl]-propionic acid;
2-[2-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-imidazol-5-yl]-acetic acid;
3-{2-[1-(2-{4-[3-(2-Chloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(2-Methoxy-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(2-Fluoro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(2,6-Dichloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(2,6-Dimethyl-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(2-Chloro-6-methyl-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-[2-(3-Methyl-1-{2-[4-(3-phenyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid;
N-Hydroxy-3-[2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionamide;
3-[2-(1-{2-[4-(3-o-Tolyl-ureido)-phenyl]-acetylamino}-but-3-enyl)-thiazol-5-yl]-propionic acid,
3-[2-(1-{2-[4-(3-o-Tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid;
N-{1-[5-(3-Methanesulfonylamino-3-oxo-propyl)-thiazol-2-yl]-3-methyl-butyl}-2-[4-(3-o-tolyl-ureido)-phenyl]-acetamide;
2-{4-[3-(2-Chloro-phenyl)-ureido]-phenyl}-N-{1-[5-(3-methanesulfonylamino-3-oxo-propyl)-thiazol-2-yl]-3-methyl-butyl}-acetamide;
3-[2-({2-[4-(3-o-Tolyl-ureido)-phenyl]-acetylamino}-methyl)-thiazol-5-yl]-propionic acid; and
3-{2-[(2-{4-[3-(2-Chloro-phenyl)-ureido]-phenyl}-acetylamino)-methyl]-thiazol-5-yl}-propionic acid.
Compounds which include the moiety of partial Formula (1.1.1):
3-[2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)4,5-dihydro-oxazol-4-yl]-propionic acid;
4-[2-(3-Methyl-1-{2-[4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)4,5-dihydro-oxazol-4-yl]-butyric acid;
3-[2-(3-Methyl-1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-oxazol-4-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methyl-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-thiazol-4-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methoxypyrid-2-yl]-ureido)-phenyl]-acetylamino}-butyl)-1,1-dioxo-4,5-dihydro-thiazol-4-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-imidazol-4-yl]-propionic acid; and
2-[2-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-imidazol-4-yl]-acetic acid.
Compounds which include the moiety of partial Formula (1.1.2):
3-[2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[4-(3-{2-methoxyphenyl}-ureido)-phenyl]-acetylamino}-butyl)-oxazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-oxazol-5-yl]-propionic acid;
4-[2-(3-Methyl-1-{2-[4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-oxazol-5-yl]-butyric acid;
2-[2-(3-Methyl-1-{2-[3-methyl-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-5-yl]-acetic acid;
3-[2-(3-Methyl-1-{2-[3-fluoro-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methoxy-4-(3-[pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methyl-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1,1-dioxo-thiazol-5-yl]-propionic acid;
4-[2-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-butyric acid;
3-[2-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-cyclopentyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-trifluoromethyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-5-yl]-propionic acid;
3-{2-[1-(2-{4-[3-(2-Chloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(2,6-Dichloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(2-Fluoro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-[2-(1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiazol-5-yl]-propionic acid;
3-{2-[1-(2-{4-[3-(2-Dimethyl-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(2-Chloro-6-methyl-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(2-Methoxy-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-{2-[1-(2-{4-[3-(Phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-propionic acid;
3-[2-(1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-butenyl)-thiazol-5-yl]-propionic acid;
3-{2-[1-(2-{4-[3-(2-Methyl-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-prop-2-enoic acid;
3-{2-[1-(2-{4-[3-(2-Methyl-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-1-hydroximino-propionic acid;
3-{2-[1-(2-{4-[3-(2-Methyl-phenyl)-ureido]-phenyl}-acetylamino)-n-butyl]-thiazol-5-yl}-propionic acid; and
3-{2-[1-(2-{4-[3-(2-Methyl-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-thiazol-5-yl}-1-methylsulfonyl-propionamide.
Compounds which include the moiety of partial Formula (1.1.3):
3-[2-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-4-yl]-propionic acid;
4-[2-(3-Methyl-1-{2-[4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-oxazol-4-yl]-butyric acid;
3-[2-(3-Methyl-1-{2-3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-4-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methyl-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-thiazol-4-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1,1-dioxo-thiazol-4-yl]-propionic acid;
3-[2-(3-Methyl-1-{2-[3-methyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-4-yl]-propionic acid; and
2-[2-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-4-yl]-acetic acid.
Compounds which include the moiety of partial Formula (1.1.4):
3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-isoxazol-5-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[4(3-{2-fluorophenyl}-ureido)-phenyl]-acetylamino}-butyl)4,5-dihydro-isoxazol-5-yl]-propionic acid;
2-[3-(3-Methyl-1-{2-[4-(3-{2-cyclopentylphenyl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-isoxazol-5-yl]-acetic acid;
4-[3-(3-Methyl-1-{2-[4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-isoxazol-5-yl]-butyric acid;
3-[3-(3-Methyl-1-{2-[4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-isoxazol-5-yl]-propionic acid; and
3-[3-(3-Methyl-1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-isoxazol-5-yl]-propionic acid.
Compounds which include the moiety of partial Formula (1.1.5):
3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)4,5-dihydro-pyrazol-1-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[4-(3-{2-methoxyphenyl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid;
4-[3-(3-Methyl-1-{2-[4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-butyric acid;
2-[3-(3-Methyl-1-{2-[3-methyl-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid;
3-[3-(3-Methyl-1-{2-[3-fluoro-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-acid;
3-[3-(3-Methyl-1-{2-[3-methoxy-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid;
4-[3-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-butyric acid;
3-[3-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[3-cyclopentyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid; and
3-[3-(3-Methyl-1-{2-[3-trifluoromethyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid;
Compounds which include the moiety of partial Formula (1.1.6):
3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[4-(3-{2-fluorophenyl}-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid;
2-[3-(3-Methyl-1-{2-[4-(3-{2-cyclopentylphenyl}-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-acetic acid;
4-[3-(3-Methyl-1-{2-[4-(3-{3-methylpyrid-2-yl}ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-butyric acid;
3-[3-(3-Methyl-1-{2-[4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid;
3-{3-[3-Methyl-1-(2-{4-[3-(4-methyl-pyridin-3-yl)-ureido]-phenyl}-acetylamino)-butyl]-isoxazol-5-yl}-propionic acid;
3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-y]-acrylic acid;
3-{3-[1-(2-{4-[3-(2-Chloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-isoxazol-5-yl}-propionic acid;
3-{3-[1-(2-{4-[3-(2-Chloro-phenyl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-isoxazol-5-yl}-3-oxo-propionic acid ethyl ester;
3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-2-oxo-propionic acid ethyl ester; and
3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-prop-2-enoic acid.
Compounds which include the moiety of partial Formula (1.1.7):
3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[4-(3-{2-methoxyphenyl}-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-propionic acid;
4-[3-(3-Methyl-1-{2-[4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-butyric acid;
2-[3-(3-Methyl-1-{2-[3-methyl-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-acetic acid;
3-[3-(3-Methyl-1-{2-[3-fluoro-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-acid;
3-[3-(3-Methyl-1-{2-[3-methoxy-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-propionic acid;
4-[3-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-butyric acid;
3-[3-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[3-cyclopentyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[3-trifluoromethyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-pyrazol-1-yl]-propionic acid.
Compounds which include the moiety of partial Formula (1.1.8):
3-[4-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-2-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-2-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[4-(3-{2-methoxyphenyl}-ureido)-phenyl]-acetylamino}-butyl)-oxazol-2-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-oxazol-2-yl]-propionic acid;
4-[4-(3-Methyl-1-{2-[4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-oxazol-2-yl]-butyric acid;
2-[4-(3-Methyl-1-{2-[3-methyl-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-2-yl]-acetic acid;
3-[4-(3-Methyl-1-{2-[3-fluoro-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-oxazol-2-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-thiazol-2-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-methyl-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1,1-dioxo-thiazol-2-yl]-propionic acid;
4-[4-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-thiazol-2-yl]-butyric acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-2-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-cyclopentyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-2-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-2-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-trifluoromethyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-2-yl]-propionic acid.
Compounds which include the moiety of partial Formula (1.1.9):
3-[4-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-imidazo-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[4-(3-{2-methoxyphenyl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-propionic acid;
4-[4-(3-Methyl-1-{2-[4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-butyric acid;
2-[4-(3-Methyl-1-{2-[3-methyl-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-acetic acid;
3-[4-(3-Methyl-1-{2-[3-fluoro-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-propionic acid;
4-[4-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-butyric acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-cyclopentyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-trifluoromethyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-imidazol-1-yl]-propionic acid
Compounds which include the moiety of partial Formula (1.1.10):
3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-1,2,4-oxadiazol-5-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[4-(3-{2-fluorophenyl}-ureido)-phenyl]-acetylamino}-butyl)-1,2,4-oxadiazol-5-yl]-propionic acid;
2-[3-(3-Methyl-1-{2-[4-(3-{2-cyclopentylphenyl}-ureido)-phenyl]-acetylamino}-butyl)-1,2,4-oxadiazol-5-yl]-acetic acid;
4-[3-(3-Methyl-1-{2-[4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1,2,4-oxadiazol-5-yl]-butyric acid;
3-[3-(3-Methyl-1-{2-[4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1,2,4-oxadiazol-5-yl]-propionic acid;
3-[3-(3-Methyl-1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-1,2,4-oxadiazol-5-yl]-propionic acid.
Compounds which include the moiety of partial Formula (1.1.11):
3-[4-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[4-(3-{2-methoxyphenyl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-propionic acid;
4-[4-(3-Methyl-1-{2-[4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-butyric acid;
2-[4-(3-Methyl-1-{2-[3-methyl-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-acetic acid;
3-[4-(3-Methyl-1-{2-[3-fluoro-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-propionic acid;
4-[4-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-butyric acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-cyclopentyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-trifluoromethyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,4-triazol-1-yl]-propionic acid.
Compounds which include the moiety of partial Formula (1.1.12):
3-[4-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[4-(3-{2-methoxyphenyl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-propionic acid;
4-[4-(3-Methyl-1-{2-[4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-butyric acid;
2-[4-(3-Methyl-1-{2-[3-methyl-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-acetic acid;
3-[4-(3-Methyl-1-{2-[3-fluoro-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-propionic acid;
4-[4-(3-Methyl-1-{2-[3-fluoro-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-butyric acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-cyclopentyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-methoxy-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-propionic acid;
3-[4-(3-Methyl-1-{2-[3-trifluoromethyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-butyl)-1H-1,2,3,4-tetrazol-1-yl]-propionic acid.
Compounds which include the moiety of partial Formula (1.1.13):
3-(3-iso-butyl-2-oxo-4-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-2-oxo-4-{[4-(3-{2-methoxyphenyl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-2-oxo-4-{[4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
4-(3-iso-butyl-2-oxo-4-{[4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetyl}piperazin-1-yl)-butyric acid;
2-(3-iso-butyl-2-oxo-4-{[3-methyl-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-acetic acid;
3-(3-iso-butyl-2-oxo-4-{[3-fluoro-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-2-oxo-4-{[3-methoxy-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
4-(3-iso-butyl-2-oxo-4-{[3-fluoro-4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-butyric acid;
3-(3-iso-butyl-2-oxo-4-{[3-methoxy-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-2-oxo-4-{[3-cyclopentyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-2-oxo-4-{[3-methoxy-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-2-oxo-4-{[3-trifluoromethyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid.
Compounds which include the moiety of partial Formula (1.1.14):
3-(3-iso-butyl-6-oxo-4-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-6-oxo-4-{[4-(3-{2-methoxyphenyl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-6-oxo-4-{[4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
4-(3-iso-butyl-6-oxo-4-{[4-(3-{3-methoxypyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-butyric acid;
2-(3-iso-butyl-6-oxo-4-{[3-methyl-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-acetic acid;
3-(3-iso-butyl-6-oxo-4-{[3-fluoro-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-6-oxo-4-{[3-methoxy-4-(3-{pyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
4-(3-iso-butyl-6-oxo-4-{[3-fluoro-4-(3-{3-methoxypyrid-2yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-butyric acid;
3-(3-iso-butyl-6-oxo-4-{[3-methoxy-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-6-oxo-4-{[3-cyclopentyl-4-(3-{3-methylpyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-6-oxo-4-{[3-methoxy-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetylamino}-piperazin-1-yl)-propionic acid;
3-(3-iso-butyl-6-oxo-4-{[3-trifluoromethyl-4-(3-{3-cyclopentylpyrid-2-yl}-ureido)-phenyl]-acetyl}-piperazin-1-yl)-propionic acid.
Compounds which include the moiety of partial Formula (1.3.0):
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(5-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(5,5-Dimethyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(3,3-Dimethyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(4-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(4-Hydroxy-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(4-Hydroxy-4-methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-azepan-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(4-Oxo-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(4-Amino-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(4-Methylamino-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(4-(Ethyl-methyl-amino)-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(2-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(3-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-oxazolidin-4-yl)-thiazol-5-yl]-propionic acid;
3-(3xe2x80x2-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-[2,4xe2x80x2]bithiazolyl-5yl)-propionic acid;
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-1,2,3,6-tetrahydro-pyridin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-piperidin-2-yl)-thiazol-5yl]-propionic acid;
3-[2-(2-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-1 2,3,4-tetrahydro-isoquinolin-3-yl)-thiazol-5-yl]-propionic acid;
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-azetidin-2-yl)-thiazol-5-yl]-propionic acid;
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-azetidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)oxazol-5-yl]-propionic acid;
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-azepan-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(5-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)oxazol-5-yl]-propionic acid;
3-[2-(5,5-Dimethyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(3-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(3,3-Dimethyl-1-{[4-(3-o-totyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)oxazol-5-yl]-propionic acid;
3-[2-(4-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)oxazol-5-yl]-propionic acid;
3-[2-(4-Hydroxy-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(4-Hydroxy-4-methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(4-Oxo-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(4-Amino-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(4-Methylamino-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(4-(Ethyl-methyl-amino)-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(2-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(3-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-oxazolidin-4-yl)oxazol-5-yl]-propionic acid;
3-[2-(3-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-thiazolidin-4-yl)-oxazol-5yl]-propionic acid;
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-1,2,3,6-tetrahydro-pyridin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-piperidin-2-yl)-oxazol-5-yl]-propionic acid;
3-[2-(2-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-3-yl)-oxazol-5-yl]-propionic acid;
3-[3-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(5-Methyl-1-{[4-(3o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5yl]-propionic acid;
3-[3-(5,5-Dimethyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-azepan-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(3-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(3,3-Dimethyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(4-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(4-Hydroxy-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(4-Hydroxy-4-methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-isoxazol-2-yl)-thiazol-5-yl]-propionic acid;
3-[3-(4-Oxo-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(4-Amino-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(4-Methylamino-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(4-(Ethyl-methyl-amino)-1-{[4-(3o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(2-Methyl-1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(3-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-oxazolidin-4-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(3-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-thiazolidin-4-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-1,2,3,6-tetrahydro-pyridin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-piperidin-2-yl)-isoxazol-5-yl]-propionic acid;
3-[3-(2-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-3-yl)-isoxazol-5-yl]-propionic acid; and
3-[3-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-azetidin-2-yl)-isoxazol-5-yl]-propionic acid.
The above-described compounds of the present invention may be utilized in the form of acids, esters, or other chemical classes of compounds to which the compounds described belong. It is also within the scope of the present invention to utilize those compounds in the form of pharmaceutically acceptable salts derived from various organic and inorganic acids and bases in accordance with procedures well known in the art. Such well-known pharmaceutically acceptable salts include, but are not limited to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, besylate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecysulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isethionate, lactate, lactobionate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, salicylate, sodium phosphate, stearate, succinate, sulfate, sulfosalicylate, tartrate, thiocyanate, thiomalate, tosylate, and undecanoate.
Base salts of the compounds of the present invention include, but are not limited to ammonium salts; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; salts with organic bases such as dicyclohexylamine, meglumine, N-methyl-D-glucamine, tris-(hydroxymethyl)-methylamine (tromethamine), and salts with amino acids such as arginine, lysine, etc. Compounds of the present invention which comprise basic nitrogen-containing groups may be quaternized with such agents as (C1-C4)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides and iodides; di(C1-C4)alkyl sulfate, e.g., dimethyl, diethyl and diamyl sulfates; (C10-C18)alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and and stearyl chlorides, bromides and iodides; and aryl-(C1-C4)alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such salts permit the preparation of both water-soluble and oil-soluble compounds of the present invention.
Among the above-recited pharmaceutical salts those which are preferred include, but are not limited to acetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate, and tromethamine.
Multiple salts forms are included within the scope of the present invention where a compound of the present invention contains more than one group capable of forming such pharmaceutically acceptable salts. Examples of typical multiple salt forms include, but are not limited to bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium, and trihydrochloride.
The pharmaceutical compositions of the present invention comprise any one or more of the above-described inhibitiory compounds of the present invention, or a pharmaceutically acceptable salt thereof as also above-described, together with a pharmaceutically acceptable carrier in accordance with the properties and expected performance of such carriers which are well-known in the pertinent art.
The term xe2x80x9ccarrierxe2x80x9d as used herein includes acceptable diluents, excipient, adjuvants and vehicles. Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this invention include but are not limited to, ion exchange compositions; alumina; aluminum stearate; lecithin; serum proteins, e.g., human serum albumin; phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, e.g., prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; e.g., sodium carboxymethylcellulose; polyethylene glycol; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; and wool fat.
More particularly, the diluents, excipient, adjuvants and vehicles used in the pharmaceutical compositions of the present invention comprise members selected from the groups consisting essentially of the following: acidifying and alkalizing agents added to obtain a desired or predetermined pH comprise acidifying agents, e.g., acetic acid, glacial acetic acid, malic acid, and propionic acid, and alkalizing agents, e.g., edetol, potassium carbonate, potassium hydroxide, sodium borate, sodium carbonate, and sodium hydroxide; aerosol propellants required where the pharmaceutical composition is to be delivered as an aerosol under significant pressure, e.g., acceptable halogenated hydrocarbons; nitrogen; or a volatile hydrocarbon such as butane, propane, isobutane or mixtures thereof; antimicrobial agents including antibacterial, antifungal and antiprotozoal agents added where the pharmaceutical composition is topically applied, e.g, antimicrobial agents such as benzyl alcohol, chlorobutanol, phenylethyl alcohol, phenylmercuric acetate, potassium sorbate, and sorbic acid, and antifungal agents such as benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, and sodium benzoate; antimicrobial preservatives added to the pharmaceutical compositions in order to protect them against the growth of potentially harmful microorganisms, e.g., alkyl esters of p-hydroxybenzoic acid, propionate salts, phenoxyethanol, methylparaben sodium, propylparaben sodium, sodium dehydroacetate, benzalkonium chloride, benzethonium chloride, and benzyl alcohol; antioxidants added to protect all of the ingredients of the pharmaceutical composition from damage or degradation by oxidizing agents present in the composition itself or the use environment, e.g., anoxomer, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, potassium metabisulfite, propyl octyl and dodecyl gallate, sodium metabisulfite, sulfur dioxide, and tocopherols; buffering agents used to maintain a desired pH of a composition once established, e.g., calcium acetate, potassium metaphosphate, potassium phosphate monobasic, and tartaric acid; and chelating agents used to help maintain the ionic strength of the pharmaceutical composition and bind to and effectively remove destructive compounds and metals, e.g., edetate dipotassium, edetate disodium, and edetic acid.
Dermatologically active agents are added to the pharmaceutical compositions of the present invention to be applied topically, e.g., wound healing agents such as peptide derivatives, yeast, panthenol, hexylresorcinol, phenol, tetracycline hydrochloride, lamin and kinetin, glucocorticosteroids for treating inflammation, e.g., hydrocortisone, dexamethasone, betamethasone, triamcinolone, fluocinolone and methylprednisolone, retinoids for treating acne, psoriasis, cutaneous aging, and skin cancer, e.g., retinol, tretinoin, isotretinoin, etretinate, acitretin, and arotinoid, immunosuppressive agents for treating inflammation, e.g., dapsone and sulfasalazine; mild antibacterial agents, e.g., resorcinol, salicylic acid, benzoyl peroxide, erythromycin-benzoyl peroxide, erythromycin, clindamycin, and mupirocin, antifungal agents, e.g., griseofulvin, azoles such as miconazole, econazole, itraconazole, fluconazole, and ketoconazole, and allylamines such as naftifine and terfinafine, antiviral agents, e.g., acyclovir, famciclovir, and valacyclovir, antihistamines, e.g., diphenhydramine, terfenadine, astemizole, loratadine, cetirizine, acrivastine, and temelastine, topical anesthetics, e.g., benzocaine, lidocaine, dibucaine, and pramoxine hydrochloride, topical analgesics, e.g., methyl salicylate, camphor, menthol, and resorcinol; topical antiseptics for preventing infection, e.g., benzalkonium chloride and povidone-iodine; vitamins and derivatives thereof such as tocopherol, tocopherol acetate, retinoic acid and retinol.
Further examples of diluents, excipient, adjuvants and vehicles used in the pharmaceutical compositions of the present invention comprise members selected from the groups consisting essentially of the following: dispersing and suspending agents, e.g., poligeenan, povidone, and silicon dioxide; emollients, e.g., hydrocarbon oils and waxes, triglyceride esters, acetylated monoglycerides, methyl and other alkyl esters of C10-C20 fatty acids, C10-C20 fatty acids, C10-C20 fatty alcohols, lanolin and derivatives, polyhydric alcohol esters such as polyethylene glycol (200-600), polyoxyethylene sorbitan fatty acid esters, wax esters, phospholipids, and sterols; emulsifying agents used for preparing oil-in-water emulsions; excipients, e.g., laurocapram and polyethylene glycol monomethyl ether; humectants, e.g., sorbitol, glycerin and hyaluronic acid; ointment bases, e.g., petrolatum, polyethylene glycol, lanolin, and poloxamer; penetration enhancers, e.g., dimethyl isosorbide, diethyl-glycol-monoethylether, 1-dodecylazacycloheptan-2-one, and dimethylsulfoxide (DMSO); preservatives, e.g., benzalkonium chloride, benzethonium chloride, alkyl esters of p-hydroxybenzoic acid, hydantoin derivatives, cetylpyridinium chloride, propylparaben, quaternary ammonium compounds such as potassium benzoate, and thimerosal; sequestering agents comprising cyclodextrins; solvents, e.g., acetone, alcohol, amylene hydrate, butyl alcohol, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, isostearyl alcohol, methyl alcohol, methylene chloride, mineral oil, peanut oil, phosphoric acid, polyethylene glycol, polyoxypropylene 15 stearyl ether, propylene glycol, propylene glycol diacetate, sesame oil, and purified water; stabilizers, e.g., calcium saccharate and thymol; surfactants, e.g., lapyrium chloride; laureth 4, i.e., a-dodecyl-xcfx89-hydroxy-poly(oxy-1,2-ethanediyl) or polyethylene glycol monododecyl ether.
According to this invention, the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Rh, HClX or similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation, as described above, or in a suitable enema formulation. Topically active transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspension in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, hydrofluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which the ingredient is co-administered.
The dosage and dose rate of the compounds of this invention effective for preventing, inhibiting, suppressing or reducing cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4 will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the observations and conclusions of the treating physician.
For example, where the dosage form is oral, e.g., a tablet or capsule, suitable dosage levels of the compounds of Formula (1.0.0) will be between about 1.0 xcexcg and about 10.0 mg/kg body weight per day, preferably between about 5.0 xcexcg and about 5.0 mg/kg body weight per day, more preferably between about 10.0 xcexcg and about 1.0 mg/kg of body weight per day, and most preferably between about 20.0 xcexcg and about 0.5 mg/kg of body weight per day of the active ingredient.
Where the dosage form is topically administered to the bronchia and lungs, e.g., by means of a powder inhaler or nebulizer, suitable dosage levels of the compounds of Formula (1.0.0) will be between about 0.1 xcexcg and about 1.0 mg/kg body weight per day, preferably between about 0.5 xcexcg and about 0.5 mg/kg body weight per day, more preferably between about 1.0 xcexcg and about 0.1 mg/kg of body weight per day, and most preferably between about 2.0 xcexcg and about 0.05 mg/kg of body weight per day of the active ingredient.
Using representative body weights of 10 kg and 100 kg in order to illustrate the range of daily topical dosages which might be used as described above, suitable dosage levels of the compounds of Formula (1.0.0) will be between about 1.0-10.0 xcexcg and 10.0-100.0 mg per day, preferably between about 5.0-50.0 xcexcg and 5.0-50.0 mg per day, more preferably between about 10.0-100.0 xcexcg and 1.0-10.0 mg per day, and most perferably between about 20.0-200.0 xcexcg and about 0.5-5.0 mg per day of the active ingredient comprising a compound of Formula (1.0.0). These ranges of dosage amounts represent total dosage amounts of the active ingredient per day for a given patient. The number of times per day that a dose is administered will depend upon such pharmacological and pharmacokinetic factors as the half-life of the active ingredient, which reflects its rate of catabolism and clearance, as well as the minimal and optimal blood plasma or other body fluid levels of said active ingredient attained in the patient which are required for therapeutic efficacy.
Numerous other factors must also be considered in deciding upon the number of doses per day and the amount of active ingredient per dose which will be administered. Not the least important of such other factors is the individual respsonse of the patient being treated. Thus, for example, where the active ingredient is used to treat or prevent asthma, and is administered topically via aerosol inhalation into the lungs, from one to four doses consisting of acuations of a dispensing device, i.e., xe2x80x9cpuffsxe2x80x9d of an inhaler, will be administered each day, each dose containing from about 50.0 xcexcg to about 10.0 mg of active ingredient.
Included within the scope of the present invention are embodiments comprising compositions which contain, in addition to a compound of the present invention as active ingredient, additional therapeutic agent active ingredients selected from the group consisting essentially of anti-inflammatory corticosteroids; bronchodilators; antiaasthmatics; non-steroidal anti-inflammatories; immunosuppressants; immunostimulants; antimetabolites; antipsoriatics and antidiabetics. Specific compounds within each of these classes may be selected from those listed under the appropriate headings in Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, England, pp. 970-986 (1990); and Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 9th ed., Hardman, J. G. and Limbird, L. E., eds., McGraw-Hill, 1996, the disclosure of which are incorporated herein by reference in their entireties. Especially preferred active ingredients to be included for use in combination with the compounds of Formula (1.0.0) are anti-inflammatory compounds such as theophylline, sulfasalazine and aminosalicylates; immunosuppressants such as cyclosporin, FK-506, and rapamycin; antimetabolites such as cyclophosphamide and methotrexate; and immunomodulators such as the interferons.
Still further embodiments of the present invention relate to a method of treating or preventing an inflammatory, autoimmune or respiratory disease by inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4. As already mentioned,. VLA-4-associated cell adhesion plays a central role in a variety of inflammatory, immune and autoimmune diseases. Thus, inhibition of cell adhesion by the compounds of this invention may be utilized in methods of treating or preventing inflammatory, immune and autoimmune diseases. Preferably the diseases to be treated with the methods of this invention are selected from asthma, arthritis, psoriasis, transplantation rejection, multiple sclerosis, diabetes and inflammatory bowel disease.
The above-described methods of treatment of the present invention may employ the compounds of Formula (1.0.0) in the form of monotherapy, but said methods may also be used in the form of multiple therapy in which one or more compounds of Formula (1.0.0) are coadministered in combination with a known anti-inflammatory, immunomodulating, immunostimulating or immunosuppressive agent. The terms xe2x80x9ccoadministeredxe2x80x9d or xe2x80x9ccoadministrationxe2x80x9d as used herein are intended to mean therapeutic utilization of one or more compounds of Formula (1.0.0) in combination with one or more additional therapeutic agents, including but not limited to, administration of the combination of therapeutic active agents in a single dosage form or in multiple dosage forms representing the same or different routes of administration, said multiple dosage forms being administered at substantially the same time or at different times.
Subsequent to synthesis of any of the above-recited preferred species of the present invention or any other compounds falling within the scope of the present invention, the biological activities relating to the VLA-4 specificities of said compounds may be determined using one or more of the numerous in vitro and in vivo assays which have been described heretofore in the technical literature pertinent to the art. For example, some of the now very-well established assay methods and models concern measurement of VLA-4 activity by determining the concentration of a test candidate inhibitor required to block the binding of VLA-4-expressing cells to fibronectin- or CS-1 coated plates. In this assay microtiter wells are coated with either fibronectin (containing the CS-1 sequence), CS-1 peptide or soluble VCAM-1. Once the wells are coated, varying concentrations of the test compound are then added together with appropriately labelled, VLA-4-expressing cells. Alternatively, the test compound may be added first and allowed to incubate with the coated wells prior to the addition of the cells. The cells are allowed to incubate in the wells for at least 30 minutes. Following incubation, the wells are emptied and washed. Inhibition of binding is measured by quantitating the fluorescence or radioactivity bound to the plate for each of the various concentrations of test compound, as well as for controls containing no test compound. However, the assay just described is less preferred than other assays mentioned further below in determining the VLA-4 activity of the compounds of Formula (1.0.0).
VLA-4-expressing cells that may be utilized in this assay include Ramos cells, Jurkat cells, A375 melanoma cells, as well as human peripheral blood lymphocytes (PBL). The cells used in this assay may be fluorescently or radioactively labelled.
In order to assess the VLA-4 inhibitory specificity of test compounds, assays for other major groups of integrins, i.e., xcex22 and xcex23, as well as other xcex21 integrins, such as VLA-5, VLA-6 and xcex14xcex27 may be performed. These assays may be similar to the adhesion inhibition and direct binding assays described above, substituting the appropriate integrin-expressing cell and corresponding ligand. For example, polymorphonuclear cells (PMNs) express xcex22 integrins on their surface and bind to ICAM; while xcex23 integrins are involved in platelet aggregation and inhibition may be measured in a standard platelet aggregation assay. VLA-5 binds specifically to Arg-Gly-Asp sequences, while VLA-6 binds to laminin. Further, xcex14xcex27 is a recently discovered homologue of VLA-4, which also binds fibronectin and VCAM as well as MAdCAM-1. Specificity with respect to xcex14xcex27 is determined in a binding assay that utilizes CS-1, VCAM or MAdCAM-1 and a cell line that expresses xcex14xcex27, but not VLA-4, such as RPMI-8866 cells.
Once VLA-4-specific inhibitors are identified, they may be further characterized in in vivo assays. One such assay tests the inhibition of allergen induced airway hyperresponsiveness and cell influx, such as described by Henderson et al., xe2x80x9cBlockade of CD49d (xcex14 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthmaxe2x80x9d, J. Clin. Invest., 100(12), pp. 3083-92 (1997). In this assay, mice are sensitized by ip exposure to an irritant, such as ovalbumin. Following a recovery period, the mice are challenged by aerosol exposure to the allergen. Before aerosol exposure, the mice are given various doses of the VLA-4 inhibitor by intratracheal injection. In vivo inhibition of cell adhesion associated inflammation is assessed by measuring the number of cells and cytokines in the bronchial alveolar lavage fluid. In this manner, one may identify those inhibitors of this invention which are best suited for inhibiting inflammation.
Another in vivo assay that may be employed the primate asthma assay. This assay is performed essentially as described in Turner, C. R., et al., xe2x80x9cCharacterization of a primate model of asthma using anti-allergy/anti-asthma agentsxe2x80x9d, Inflammation Research, 45(5), pp. 239-45 (1996), the disclosure of which is incorporated herein by reference in its entirety. This assay measures inhibition of Ascaris antigen-induced late phase airway responses and airway hyperresponsiveness in allergic primates following administration of anti-allergy/anti-asthma agents.
The compounds of the present invention may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation (metered dose inhaler, dry powder inhaler or nebulizer), topically, rectally, nasally, intraocularly, buccally, vaginally or via an implanted reservoir. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
The compounds of Formula (1.0.0) may be prepared in accordance with well-known procedures for carrying out the synthesis of organic compounds which are non-peptidyl or semi-peptidyl in nature. A number of different procedures are available which are fully disclosed in the technical literature and with which the skilled artisan will be familiar. The description which follows of several such synthesis schemes is merely representative and not intended to be in any way limiting. A number abbreviations are used in said description in order to conserve space. Although these abbreviations are also well known to the artisan, they are set out immediately below for clarity and convenience:
A group of preferred A components of the compounds of Formula (1.0.0) have been described above and illustrated by partial formulas (IVb) through (IVu). The most basic of these components is that of Formula (IVc), i.e., 4-(Nxe2x80x2-phenylurea)-phenylmethyl. The following schematic synthesis diagram illustrates a generalized preparation process for the compounds of Formulas (1.4.0)-(1.4.20): 
The starting material Ar-NCO is an isocyanate in which xe2x80x9cArxe2x80x9d has the same definition as the A component of Formula (1.0.0) regarding the aryl, heteroaryl and heterocyclyl moieties substituted with 0 to 3 R10. Isocyanate starting materials for making component A as represented by partial Formulas (1.4.1) through (1.4.20) are commercially available, e.g., from Aldrich Chemical Company, Milwaukee, Wis. 53233, as follows:
Pyridyl analogues of the above phenyl isocyanates can be used to prepare the corresponding compounds of Formula (1.0.0) where the A component contains a pyridyl group.
One of the above-described isocyantes is reacted with an aryl-, heteroaryl- or heterocyclyl-acetic acid having an amine group at the 4-position. The addition of amines to isocyanates is a well-known reaction which provides substituted ureas in a facile manner. The reaction can be carried out in a solvent such as methylene chloride with triethylamine at slightly elevated temperatures. The reactant used to produce the majority of the A components illustrated as partial Formulas (1.4.1)-(1.4.20) is 4-aminophenylacetic acid, commercially available from the above-mentioned Aldridge Chemical Company.
The disubstituted urea (2.1.2) prepared as in the above-indicated reaction scheme, which forms the reactant eventually resulting in component A of the compounds of Formula (1.0.0), is next reacted with the reactant eventually resulting in component B, one of the partial Formulas (1.1.0)-(1.1.14). For example, the B component reactant may be that of partial Formula (1.7.0) illustrated below in Formula (IIIo-a): 
Component B reactants of the type illustrated in Formula (IIIo-a) may be prepared in accordance with procedures well-known in the technical literature of the relevant art. For example, see Bhatt, U.; Mohamed, N.; Just, G.; Tetrahedron Lett., 1997, 38(21), 3679-3682; and Sugihara, H. et al., J. Med. Chem., 1998, 41, 489-502.
The reaction between the component A forming reactant and the component B forming reactant will be recognized by the artisan as one involving the acylation of an amine by a carboxylic acid which can be made to proceed in good yield at room temperature or slightly above by the use of coupling agents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT); dicyclohexylcarbodiimide (DCCI); N,Nxe2x80x2-carbonyldiimidazole; POCI3; TiCI4; SO2CIF; Ti(OBu)4; P2I4; BU3N; benzotriazol-1-yl diethyl phosphate; N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl(succinimido)uronium tetrafluoroborate; and preferably di-iso-propylethyl amine (DIEA) and benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP). This reaction may be illustrated in the following schematic synthesis diagram which provides a generalized preparation process for the compounds of Formulas (1.0.0): 
The piperazinyl reactant (2.1.3) for component B is used in the form of the (C1-C4)alkyl ester of the acid, which serves as a blocking group to prevent reaction of the carboxylic acid group with the secondary amine group forming part of the piperazinyl moiety of other reactants (2.1.3) present in the reaction mixture. The coupling agents promote condensation of reactants (2.1.2) and (2.1.3) to provide intermediate (2.1.4), which is a compound of Formula (1.0.0) where R is defined as O(C1-C6)alkyl. To prepare the final product of Formula (1.0.0) in the form of the acid, an additional step is required, as is shown in the following reaction scheme: 
The aqueous hydroxide saponification is carried out in an alcohol solvent, preferably tert-butanol as indicated. Subsequent neutralization is preferably carried out using 1N HCl as the aqueous mineral acid, and the reaction is conveniently carried out at room temperature.
The above-described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme 1-xcex1, Steps A through C with reference to a particular compound of the present invention: 
Compounds of Formula (1.0.0) in which the B component is a moiety of partial Formula (1.1.4), i.e., an isoxazolyl group, may be prepared by a method in which the final two steps are similar to the final two steps, Steps B and C, of the method illustrated in Synthetic Scheme I. Preparation of the amine reactant which produces component B of partial Formula (1.4.4) is illustrated generally for the compounds of Formula (1.0.0) in the following Synthesis Scheme IIxe2x80x94Step A: 
In Step A of this synthesis, the starting material is a 1-formyl derivative of a carbamic acid having a protecting group R, and having the desired R2 and R3 substituents, of the formula: ROC(xe2x95x90O)NHC(R2)(R3)CH(xe2x95x90O). This aldehyde starting material is reacted with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as water and methanol to prepare the corresponding oxime in accordance with a well-known procedure involving carbonyl addition and elimination of water in which an optimal pH of about 4 is maintained. 
The oxime (hydroxyiminomethyl) intermediate (2.1.7) is converted to the desired isoxazolyl-containing B component of partial Formula (IIIe), intermediate (2.1.8), by oxidizing (2.1.7) to its corresponding nitrile N-oxide with sodium hypochlorite in a suitable solvent such as THF or methylene chloride; and reacting the nitrile N-oxide in situ with an appropriate terminal alkyl alkenoate. This [2+3] cycloaddition reaction is well known in the literature as a method for preparing the isoxazoline ring structure. See, e.g., Synthesis, 508-9, 1982. 
The benzyl carbamate (2.1.8) is converted to the primary amine (2.1.9) by utilizing one of the following reagents using the published literature procedures: H2/Pd-C (Ber., 65, p. 1192, 1932); HBr, AcOH (J. Org. Chem., 17, p. 1564, 1952); 70% HF, pyridine (J. Chem. Soc., Chem. Commun., p. 451, 1976) or CF3SO3H (J. Chem. Soc., Chem. Commun., p. 107, 1974).
The above described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme II, Steps A through D with reference to a particular compound of the present invention (where Step D is analogous to Steps B and C in Scheme I): 
Compounds of Formula (1.0.0) in which the B component is a moiety of partial Formula (1.1.6), i.e., an isoxazole group, may be prepared by a method in which the final two steps are similar to Steps B and C of the method illustrated in Synthetic Scheme I. Preparation of the amine reactant which produces component B of partial Formula (1.1.6) is illustrated generally for the compounds of Formula (1.0.0) in the following synthesis scheme: 
The oxime (hydroxyiminomethyl) intermediate (2.1.7) is converted to the desired isoxazole-containing B component of partial Formula (1.1.6), intermediate (2.1.11), by oxidizing (2.1.7) to its corresponding nitrile N-oxide with sodium hypochlorite in a suitable solvent such as THF or methylene chloride; and reacting the nitrile N-oxide in situ with an appropriate terminal alkyl alkynoate. This [2+3] cycloaddition reaction is well known in the literature as a method for preparing the isoxazole ring structure. See, e.g., Synthesis, 508-9, 1982. 
The benzyl carbamate (2.1.11) is converted to the primary amine (2.1.12) by utilizing one of the following reagents using the published literature procedures: H2/Pd-C (Ber., 65, p. 1192, 1932); HBr, AcOH (J. Org. Chem., 17, p. 1564, 1952); 70% HF, pyridine (J. Chem. Soc., Chem. Commun., p. 451, 1976) or CF3SO3H (J. Chem. Soc., Chem. Commun., p. 107, 1974).
The above described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme III, Steps A through C with reference to a particular compound of the present invention (where Step C is analogous to Steps B and C in Scheme I): 
Compounds of Formula (1.0.0) in which the B component is a moiety of partial Formula (1.1.0)), i.e., an oxazoline group, may be prepared by a method illustrated generally in the following synthesis scheme: 
The condensation of carboxylic acid (2.1.2) and amine (2.1.14) to give the tert-butyl ester (2.1.15) is shown in Step A, and is analogous to the reaction in Synthesis Scheme 1, Step B. The tert-butyl ester is converted to its corresponding acid, (2.1.16), by subjecting it to acidic conditions such as HCl in a solvent such as dioxane at or near room temperature. The transformation of (2.1.15) to (2.1.16) is shown in Step B below. 
Intermediate acid (2.1.16) is condensed with amine (2.1.17) to give amide (2.1.18) as shown is Step C below, and is analogous to the reaction in Synthesis Scheme 1, Step B. Intermediate amide 19(2.1.18) is cyclized to oxazoline (2.1.19) in the presense of diethylaminosulfur trifluoride (DAST) as shown below in Step D using literature procedures (Pinto et al., Tetrahedron Lett. 30, p. 3349, 1989; Jones et al. Tetrahedron Lett. 31, p. 3649, 1989). 
Finally, the desired acid (2.1.20) is obtained from ester (2.1.19) in the presence of aqueous base as shown is Step E below and is analogous to the reaction in Synthesis Scheme 1, Step C. 
The above described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme IV, Steps A through E with reference to a particular compound of the present invention: 
Compounds of Formula (1.0.0) in which the B component is a moiety of partial Formula (1.1.2), i.e., an oxazole group, may be prepared by a method illustrated generally in the following synthesis scheme: 
Intermediate acid (2.1.22) is condensed with amine (2.1.23) to give amide (2.1.24) as shown is Step A, and is analogous to the reaction in Synthesis Scheme I, Step B. Intermediate amide (2.1.24) is cyclized to oxazole (2.1.25) in the presense of phosphorous oxychloride in a solvent such as toluene at temperatures between room temperature and 110xc2x0 C. as shown in Step B below (J. Org. Chem. 55, p.386, 1990). 
The benzyl carbamate (2.1.25) is converted to the primary amine (2.1.26) by utilizing one of the following reagents using the published literature procedures: H2/Pd-C (Ber., 65, p. 1192, 1932); HBr, AcOH (J. Org. Chem., 17, p. 1564, 1952); 70% HF, pyridine (J. Chem. Soc., Chem. Commun., p. 451, 1976) or CF3SO3H (J. Chem. Soc., Chem. Commun., p. 107, 1974). Amine intermediate (2.1.26) is converted to compounds of Formula (1.0.0) by using reactions analogous to Synthesis Scheme I, Steps B and C. 
The above described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme V, Steps A through C with reference to a particular intermediate compound of the present invention: 
Compounds of Formula (1.0.0) in which the B component is a moiety of partial Formula (1.1.2), i.e., a thiazole group, may be prepared by a method illustrated generally in the following synthesis scheme: 
Intermediate amide (2.1.24) is cyclized to thiazole (2.1.27) using the literature conditions of Lawesson""s Reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] in a solvent such as toluene at temperatures between room temperature and 110xc2x0 C. as shown in Step A. The benzyl carbamate (2.1.27) is converted to the primary amine (2.1.28) as shown in Step B by utilizing one of the following reagents using the published literature procedures: H2/Pd-C (Ber., 65, p. 1192, 1932); HBr, AcOH (J. Org. Chem., 17, p. 1564, 1952); 70% HF, pyridine (J. Chem. Soc., Chem. Commun., p. 451, 1976) or CF3SO3H (J. Chem. Soc., Chem. Commun., p. 107, 1974). Amine intermediate (2.1.28) is converted to compounds of Formula (1.0.0) by using reactions analogous to Synthesis Scheme I, Steps B and C. 
The above described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme VI, Steps A and B with reference to a particular intermediate compound of the present invention: 
Compounds of Formula (1.0.0) in which the B component is a moiety of partial Formula (1.3.0), e.g., a pyrrolidin-2-yl-thiazol-5-yl group, may be prepared by a method illustrated generally in the following synthesis scheme: 
The pyrrolidine dicarboxylic acid (2.3.0) as a protected diester is condensed with amine (2.3.1) to give amide (2.3.2) under reaction conditions which are analogous to those above-described in Synthesis Scheme I, Step B. The amide (2.3.2) is next cyclized to the thiazole (2.3.3) using Lawesson""s Reagent under conditions well known in the art and described in detail further herein. This reaction is illustrated in Synthesis Scheme VII, Step B as follows: 
The thiazole (2.3.3) prepared as above described now contains the pyrrolidin-2-yl-thiazol-5-yl component which is a key part of the compounds of Formula (1.0.0) in which the B component is a moiety of partial Formula (1.3.0). The remaining components of a compound of Formula (1.0.0) are prepared in the succeeding steps illustrated below. The nitrogen atom of the pyrrolidinyl group is deprotected to form the pyrrolidinyl-thiazole (2.3.4), followed by condensation of (2.3.4) with an o-tolyl-ureido-phenyl acetic acid reactant (2.3.5) which provides the left-hand portion of a compound of the present invention. There is thereby formed an xe2x80x9cRxe2x80x9d ester of a compound of Formula (1.0.0), (2.3.6), as shown in Synthesis Scheme VII, Step C as follows: 
In a final step the ester (2.3.6) is reduced to give the corresponding catboxylic acid (2.3.7) in accordance with well-known procedures. This step is illustrated as Synthesis Scheme VII, Step D, as follows: 